Multi-layered coatings and methods for controlling elution of active agents

ABSTRACT

Embodiments of the invention include multi-layered coatings for controlling the elution rates of active agents and methods. In an embodiment, the invention includes a method of applying an elution control coating to a substrate. The method can include depositing a coating solution onto the substrate to form a base layer. The method can also include selecting a desired concentration of the solvent based on a desired elution rate. The method can further include removing solvent from the base layer to reach a desired concentration of the solvent and depositing a layer of parylene on the base layer. In an embodiment, the invention can include a medical device including a substrate, a base layer, and a porous layer. The base layer can include a polymeric matrix and an active agent dispersed within the polymeric matrix. The porous layer can include parylene. Other embodiments are also included herein.

This application claims the benefit of U.S. Provisional Application No.60/826,823, filed Sep. 25, 2006, the content of which is hereinincorporated by reference.

FIELD OF THE INVENTION

The present invention relates to coatings and methods for controllingthe elution of active agents. More specifically, the present inventionrelates to multi-layered coatings and methods for controlling theelution of active agents.

BACKGROUND OF THE INVENTION

Active agent elution control coatings are now commonly used to deliveractive agents to tissues of the body. Elution control coatings canenable the delivery of an active agent over a period of time in order tooptimize therapeutic effect. In addition, when disposed on a medicaldevice, elution control coatings can enable site-specific active agentdelivery because the medical device can be positioned as desired withinthe body of a patient.

A desirable elution rate for an active agent in one treatment scenariomay be different than a desirable elution rate for an active agent inanother treatment scenario. Therefore, it can be advantageous to be ableto manipulate or change the elution kinetics of a coating in order tomore closely match what is desirable for a specific treatment scenario.

Active agents delivered from elution control coatings can include manydifferent types of compounds including small hydrophilic molecules,small hydrophobic molecules, macromolecules such as carbohydrates,peptides, proteins, and the like. Of these compounds, peptides andproteins can pose a challenge because, in general, they are susceptibleto denaturation. In addition, the unique properties of peptides andproteins, such as their relatively large size, can frequently result inthem being delivered either more quickly or more slowly than desired.

Accordingly, there is a need for coatings that can deliver active agentsat desirable rates and methods of making the same. There is also a needfor coatings that can be used to control the elution rate ofmacromolecules such as peptides and proteins.

SUMMARY OF THE INVENTION

Embodiments of the invention include multi-layered coatings forcontrolling the elution rates of active agents and methods of making thesame. In an embodiment, the invention includes a method of applying anelution control coating to a substrate. The method can includedepositing a coating solution onto the substrate to form a base layer,the coating solution including an active agent, a polymer, and asolvent. The method can also include selecting a desired concentrationof the solvent based on a desired elution rate. The method can furtherinclude removing solvent from the base layer to reach a desiredconcentration of the solvent and depositing a layer of parylene on thebase layer.

In an embodiment, the invention can include a method of depositing amulti-layer elution control coating onto a substrate. The method caninclude depositing a coating solution onto the substrate to form a baselayer, the coating solution including an active agent, a polymer, and asolvent. The method can also include storing the substrate and baselayer under vacuum for a period of time greater than about 30 minutes toform a degassed base layer and depositing a layer of parylene on thedegassed base layer.

In an embodiment, the invention can include a medical device including asubstrate, a base layer, and a porous layer. The base layer can bedisposed on the substrate. The base layer can include a polymeric matrixand an active agent. The active agent can be dispersed within thepolymeric matrix. The active agent can be selected from the groupconsisting of peptides, proteins, antibodies, and antibody derivatives.The porous layer can be disposed on the base layer. The porous layer caninclude parylene.

This summary is an overview of some of the teachings of the presentapplication and is not intended to be an exclusive or exhaustivetreatment of the present subject matter. Further details are found inthe detailed description and appended claims. Other aspects will beapparent to persons skilled in the art upon reading and understandingthe following detailed description and viewing the drawings that form apart thereof, each of which is not to be taken in a limiting sense. Thescope of the present invention is defined by the appended claims andtheir legal equivalents.

BRIEF DESCRIPTION OF THE FIGURES

The invention may be more completely understood in connection with thefollowing drawings, in which:

FIG. 1 is a cross-sectional view of a multi-layered coating system inaccordance with an embodiment of the invention.

FIG. 2 is a cross-sectional view of a multi-layered coating system inaccordance with another embodiment of the invention.

FIG. 3 is a cross-sectional view of a multi-layered coating system inaccordance with another embodiment of the invention.

FIG. 4 is a perspective view of a stent coated with a multi-layeredcoating system in accordance with an embodiment of the invention.

FIG. 5 is a perspective view of a coil coated with a multi-layeredcoating system in accordance with an embodiment of the invention.

FIG. 6 is a graph showing elution of IgG from a medical device into atest solution over time.

FIG. 7 is a graph showing elution of IgG from a medical device into atest solution over time.

While the invention is susceptible to various modifications andalternative forms, specifics thereof have been shown by way of exampleand drawings, and will be described in detail. It should be understood,however, that the invention is not limited to the particular embodimentsdescribed. On the contrary, the intention is to cover modifications,equivalents, and alternatives falling within the spirit and scope of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

The embodiments of the present invention described herein are notintended to be exhaustive or to limit the invention to the precise formsdisclosed in the following detailed description. Rather, the embodimentsare chosen and described so that others skilled in the art canappreciate and understand the principles and practices of the presentinvention.

All publications and patents mentioned herein are hereby incorporated byreference. The publications and patents disclosed herein are providedsolely for their disclosure. Nothing herein is to be construed as anadmission that the inventors are not entitled to antedate anypublication and/or patent, including any publication and/or patent citedherein.

As described above, a desirable elution rate for an active agent in onetreatment scenario may be different than a desirable elution rate for anactive agent in another treatment scenario. Therefore, it can beadvantageous to be able to manipulate or change the elution rate of acoating to optimize treatment.

Elution of some active agents, such as peptides and proteins, fromcoatings can pose a particular challenge. The activity of peptides andproteins is typically dependent on their three-dimensional structurewhich can be disrupted by heat, solvents, changing ionic concentrations,shearing forces, etc. Therefore, such active agents need to be handledcarefully to preserve their activity. In addition, the size of peptidesand proteins can make it difficult to elute them from a coating at adesirable rate. Frequently, elution control coatings elute such activeagents either too quickly or too slowly.

The polymer known as parylene usually forms a continuous barrier to thepassage of molecules. Because of its barrier properties, parylene hasfound many industrial uses including as a protective coating onelectronic equipment. However, as shown herein, a multilayered coatingincluding a top coat of parylene can be manipulated so that it providesa desirable elution rate of an active agent such as a peptide orprotein. While not intending to be bound by theory, it is believed thatif a parylene layer is applied while a component, such as a solvent, isout-gassing from the underlying surface, the resulting parylene layerbecomes porous and can be used to control the elution of active agentssuch as peptides and proteins. As shown in example 2 below, the elutionrate of a coating can be manipulated by controlling the amount of avaporizable component, such as a solvent, in the coating layer before alayer of parylene is applied, such as by drying under vacuum, degassing,or another like technique for removing the vaporizable component.

In an embodiment, the invention includes a method of applying an elutioncontrol coating to a substrate including depositing a coating solutiononto the substrate to form a base layer, the coating solution comprisingan active agent, a polymer, and a solvent; selecting a desiredconcentration of the solvent based on a desired elution rate; removingsolvent from the base layer to reach the desired concentration of thesolvent; and depositing a top layer on the base layer, the top layercomprising parylene.

Some polymers used to make elution control matrices are relativelyhydrophobic. Hydrophobic polymers can have various properties that areconducive to creating elution control coatings with desirable releaseproperties. However, some active agents, such as peptides and proteins,may elute from a hydrophobic polymer matrix more quickly than desiredfor certain applications. Deposition of a parylene layer over ahydrophobic polymer matrix can serve to slow down the elution rate of anactive agent. Exemplary hydrophobic polymers are described more fullybelow.

In an embodiment, the invention includes a medical device including asubstrate; a base layer disposed on the substrate, the base layercomprising a hydrophobic polymeric matrix and an active agent, theactive agent dispersed within the hydrophobic polymeric matrix, theactive agent comprising a macromolecule; and a top layer disposeddirectly on the base layer, the top layer comprising parylene and havinga thickness of between about 0.01 microns and about 5 microns.

Elution control matrices including both degradable and non-degradablepolymers can offer various advantages. By way of example, combinationdegradable/non-degradable matrices can have structural integritysufficient to prevent portions of the coating from breaking off orotherwise separating under the conditions of use. Combinationdegradable/non-degradable matrices of the invention can alsoadvantageously preserve activity of an active agent eluted from thecombination degradable/non-degradable matrix. Deposition of a parylenelayer over a combination degradable/non-degradable matrix can serve tofurther increase the structural integrity of the resulting coating.Further, deposition of a parylene layer over a combinationdegradable/non-degradable matrix can provide an additional means ofcontrolling the elution rate of an active agent eluted from the coating.

In an embodiment, the invention includes a medical device including asubstrate; a base layer disposed on the substrate, the base layercomprising a polymeric matrix and an active agent, the polymer matrixincluding a degradable polymer and a non-degradable polymer, the activeagent dispersed within the polymeric matrix, the active agent comprisinga macromolecule; and a top layer disposed on the active agent layer, thetop layer comprising parylene and having a thickness of between about0.01 microns and about 5 microns.

Referring now to FIG. 1, a cross-sectional view of a multi-layer elutioncontrol coating 100 is shown in accordance with an embodiment of theinvention. A base layer 104 is disposed on a substrate 106. Thesubstrate 106 can include various components as described more fullybelow. The base layer 104 may include one or more degradable polymers,one or more non-degradable polymers, or combinations of both. In someembodiments, the base layer 104 includes a degradable polymerinterspersed with a non-degradable polymer. In some embodiments the baselayer 104 includes a hydrophobic polymer. One or more base layers can beincluded. In some embodiments, multi-layer elution control coatings caninclude a first base layer and a second base layer, the second eitherthe same or different than the first. In some cases, a differentmaterial is disposed between the base layer 104 and the substrate 106.Exemplary degradable and non-degradable polymers are described in moredetail below.

The base layer 104 can also include one or more active agents. In someembodiments, an active agent is dispersed within the base layer 104. Asused herein, the term “dispersed” shall refer to the property of beingdistributed in a soluble or insoluble state. As used herein, the term“active agent” means a compound that has a particular desired activity.For example, an active agent can be a therapeutic compound that exerts aspecific activity on a subject. Exemplary active agents can includepeptides, proteins, carbohydrates, nucleic acids, lipids,polysaccharides, synthetic inorganic or organic molecules, orcombinations thereof that cause a desired biological effect whenadministered to an animal, including but not limited to birds andmammals, including humans.

Active agents used with the invention can specifically include proteins,protein fragments, peptides, polypeptides, and the like. Peptides caninclude any compound containing two or more amino-acid residues joinedby amide bonds formed from the carboxyl group of one amino acid and theamino group of the next one. By way of example, peptides can includeglycosylated proteins, antibodies (both monoclonal and polyclonal),antibody derivatives (including diabodies, f(ab) fragments, humanizedantibodies, etc.), cytokines, growth factors, receptor ligands, enzymes,and the like. In some embodiments, the active agent is selected from thegroup consisting of peptides and proteins. In some embodiments, theactive agent is a macromolecule. Macromolecules can include moleculeshaving a molecular weight of greater than about 10 kDa. The base layer104 can be configured to control the rate at which the active agent iseluted there from.

The base layer 104 can also include one or more solvents. Solvents canbe used to aid in the process of depositing one or more polymers and oneor more active agents in the base layer. Solvents can include both polarand non-polar solvents. Solvents can include components that arevaporizable. As used herein, the term “vaporizable” shall refer tocomponents having the property of forming a vapor or gas underconditions that can include ambient or elevated temperatures andatmospheric or vacuum pressures. In some embodiments, the base layer 104can include one or more volatile components. Solvents can include water,alcohols (e.g., methanol, butanol, propanol, and isopropanol (isopropylalcohol)), alkanes (e.g., halogenated or unhalogenated alkanes such aschloroform, hexane, and cyclohexane), amides (e.g., dimethylformamide),ethers (e.g., THF and dioxolane), ketones (e.g., methylethylketone),aromatic compounds (e.g., toluene and xylene), nitriles (e.g.,acetonitrile) and esters (e.g., ethyl acetate). In some embodiments, oneor more polymers of the base layer 104 are soluble in the solvent. Insome embodiments, one or more active agents of the base layer 104 aresoluble in the solvent. The solvent can be non-polymeric.

The base layer 104 can be deposited onto the substrate 106 using any ofa variety of coating techniques including dip-coating, spray-coating(including both gas-atomization and ultrasonic atomization), fogging,brush coating, press coating, blade coating, and the like. The baselayer 104 may be applied as a coating solution and may be applied underconditions where atmospheric characteristics such as relative humidity,temperature, gaseous composition, and the like are controlled. In someembodiments, the coating solution is applied using a spray technique.Exemplary spray coating equipment that can be used to apply componentsof the invention can be found in U.S. Pat. No. 6,562,136; U.S. Pat. No.7,077,910; U.S. Pub. App. No. US 2004/0062875; U.S. Pub. App. No.2005/0158449; U.S. Pub. App. No. 2006/0088653; U.S. Pub. App. No.2005/0196424; and U.S. Pub. App. No. 2007/0128343, the contents of whichare all hereby incorporated by reference.

The thickness of the base layer 104 can depend on many factorsincluding, for example, the specific polymers used in the matrix, thedesired loading of active agent within the base layer 104, the type ofmedical device being coated, etc. In some embodiments, the base layer104 is from about 0.5 microns to about 500 microns thick.

A top layer 102 is disposed on the base layer 104. In some embodiments,the top layer 102 is disposed directly upon the base layer 104. In otherembodiments, a different material or layer is disposed between the toplayer 102 and the base layer 104. The top layer 102 can compriseparylene. The term “parylene” as used herein shall refer to a polymerbelonging to the group of polymers based on p-xylylene (substituted orunsubstituted). Parylenes have the repeating structure-(p-CH₂—C₆H₄—CH₂)_(n)—. Common parylene polymers includepoly(2-chloro-paraxylylene) (“parylene C”), poly(paraxylylene)(“parylene N”), and poly(2,5-dichloro-paraxylylene) (“parylene D”). In aparticular embodiment, the top layer 102 includespoly(2-chloro-paraxylylene) (“parylene C”). The top layer 102 can alsoinclude mono-, di-, tri-, and tetra-halo substituted polyparaxylylenes.In an embodiment, the top layer 102 includes mono-, di-, tri-, ortetra-chloro substituted polyparaxylylene. In an embodiment, the toplayer 102 includes mono-, di-, tri-, or tetra-fluoro substitutedpolyparaxylylene. Other parylene derivatives can used includingpoly(dimethoxy-p-xylylene), poly(sulfo-p-xylylene),poly(iodo-p-xylylene), poly(trifluoro-p-xylylene),poly(difluoro-p-xylylene), and poly(fluoro-p-xylylene).

Deposition of the top layer 102 can be performed using varioustechniques. In an embodiment, the top layer 102 can be deposited using avacuum vapor deposition system. In some vacuum vapor deposition systemsa polymer charge is vaporized in a vaporization chamber and then passesthrough a cracking chamber where parylene dimer vapor is cracked intoactivated monomer vapor. Vaporized activated monomer is then usuallydeposited onto a substrate in a deposition chamber. An exemplary vacuumdeposition system is the PDS-2010 LABCOTER® available from SpecialtyCoating Systems (Indianapolis, Ind.).

As shown in the examples below, the condition of the base layer 104while the top layer 102 is being deposited can affect the resultingelution rate of the multi-layer elution control coating. While notintending to be bound by theory, if the top layer 102 is applied while acomponent, such as a solvent, is out-gassing or evaporating from thebase layer 104, the parylene layer can be made porous. As such, theelution rate of an active agent from the multi-layer elution controlcoating 100 can be decreased by decreasing the amount of vaporizablecomponents therein prior to depositing the top layer 102 onto the baselayer 104. Conversely, the elution rate of an active agent from themulti-layer elution control coating 100 can be increased by increasingthe amount of vaporizable components therein prior to depositing the toplayer 102 onto the base layer 104.

The concentration of vaporizable components in the base layer 104 can beincreased or decreased in various ways. In some embodiments, a smalleramount of vaporizable components are added to a coating solution that isused to form the base layer 104. In other embodiments, vaporizablecomponents are removed from the base layer 104 after it is first appliedto a substrate. It will be appreciated that vaporizable components canbe removed from the base layer 104 in various ways. For example, thebase layer 104, as deposited onto a substrate, can simply be stored atambient temperature for a period of time. Alternatively, the base layer104 can be held at an elevated temperature for a period of time.However, elevated temperatures can contribute to degradation ordenaturation of peptides and proteins. Another method of removingvaporizable components from the base layer 104 can include storing itunder vacuum conditions for a period of time. In some embodiments, abase layer 104 disposed on a substrate is stored under vacuum for aperiod of time greater than about 30 minutes. In some embodiments, abase layer 104 disposed on a substrate is stored under vacuum for aperiod of time greater than about one hour. In some embodiments, a baselayer 104 disposed on a substrate is stored under vacuum for a period oftime greater than about twelve hours. In some embodiments, a base layer104 disposed on a substrate is stored under vacuum for a period of timegreater than about one day. In some embodiments, a base layer 104disposed on a substrate is stored under vacuum for a period of timegreater than about one week.

In addition to other aspects, the thickness of the top layer 102 canimpact the elution rate of an active agent passing the top layer 102. Ingeneral, the thicker the top layer 102 is, the slower the resultingelution rate will be. In some embodiments, the top layer 102 is fromabout 0.01 microns to about 5.0 microns thick.

In some embodiments, the base layer 104 is not disposed on a substrate.By way of example, the base layer 104 can form a bead or a film and thetop layer 102 can be disposed over the base layer 104.

FIG. 2 shows a cross-sectional view of a multi-layer elution controlcoating disposed on a substrate in accordance with another embodiment ofthe invention. A base layer 204 is disposed on a substrate 206. The baselayer 204 can include one or more polymers and/or one or more activeagents. The base layer 204 can surround the substrate 206. A top layer202 is disposed on the base layer 204. The top layer 202 can includeparylene. The top layer 202 can completely cover the base layer 204.

FIG. 3 shows a cross-sectional view of a multi-layer elution controlcoating disposed on a substrate in accordance with another embodiment ofthe invention. An underlying layer 305 is disposed on a substrate 306.The underlying layer 305 can include one or more polymers. Theunderlying layer 305 can also include one or more active agents. In someembodiments, the underlying layer 305 can be configured to elute anactive agent. In some embodiments, the underlying layer 305 includesparylene. In some embodiments, the underlying layer 305 can improveadhesion of the other layers to the substrate 306. A base layer 304 isdisposed on the underlying layer 305. The base layer 304 can include oneor more polymers and/or one or more active agents. A top layer 302 isdisposed on the base layer 304. The top layer 302 can include parylene.

Substrates

It will be appreciated that embodiments of the invention can be used inconjunction with various types of substrates. Exemplary substrates caninclude metals, polymers, ceramics, and natural materials. Metals caninclude, but are not limited to, cobalt, chromium, nickel, titanium,tantalum, iridium, tungsten and alloys such as stainless steel, nitinolor cobalt chromium. Suitable metals can also include the noble metalssuch as gold, silver, copper, platinum, and alloys including the same.

Substrate polymers include those formed of synthetic polymers, includingoligomers, homopolymers, and copolymers resulting from either additionor condensation polymerizations. Examples include, but not limited to,acrylics such as those polymerized from methyl acrylate, methylmethacrylate, hydroxyethyl methacrylate, hydroxyethyl acrylate, acrylicacid, methacrylic acid, glyceryl acrylate, glyceryl methacrylate,methacrylamide, and acrylamide; vinyls such as ethylene, propylene,styrene, vinyl chloride, vinyl acetate, vinyl pyrrolidone, andvinylidene difluoride, condensation polymers including, but are notlimited to, polyamides such as polycaprolactam, polylauryl lactam,polyhexamethylene adipamide, and polyhexamethylene dodecanediamide, andalso polyurethanes, polycarbonates, polysulfones, poly(ethyleneterephthalate), polytetrafluoroethylene, polyethylene, polypropylene,polylactic acid, polyglycolic acid, polysiloxanes (silicones),cellulose, and polyetheretherketone.

Embodiments of the invention can also include the use of ceramics as asubstrate. Ceramics include, but are not limited to, silicon nitride,silicon carbide, zirconia, and alumina, as well as glass, silica, andsapphire.

Certain natural materials can also be used in some embodiments includinghuman tissue, when used as a component of a device, such as bone,cartilage, skin and enamel; and other organic materials such as wood,cellulose, compressed carbon, rubber, silk, wool, and cotton. Substratescan also include carbon fiber. Substrates can also include resins,polysaccharides, silicon, or silica-based materials, glass, films, gels,and membranes.

Medical Devices

It will be appreciated that embodiments of the invention can be used inconjunction with, and can include, many different types of medicaldevices. For example, in FIG. 4 a perspective view of a stent 400 isshown in accordance with an embodiment of the invention. The stent 400is fabricated with a mesh-type construction and includes a plurality ofwires or struts 402 that can be made of various materials includingmetals and polymers. A multi-layer elution control coating including abase layer and a top layer can be deposited on the wires or struts 402.In FIG. 5, a perspective view of a coil 500 is shown in accordance withan embodiment of the invention. The coil 500 includes a curved wire 502that can be made of various materials including metals and polymers. Amulti-layer elution control coating including a base layer and a toplayer can be deposited on the coil 500. Specifically, a multi-layerelution control coating can be deposited on the curved wire 502.

Embodiments of the invention can include and can be used with bothimplantable devices and non-implantable medical devices. Embodiments ofthe invention can include and can be used with implantable, ortransitorily implantable, devices including, but not limited to,vascular devices such as grafts (e.g., abdominal aortic aneurysm grafts,etc.), stents (e.g., self-expanding stents typically made from nitinol,balloon-expanded stents typically prepared from stainless steel,degradable coronary stents, etc.), catheters (including arterial,intravenous, blood pressure, stent graft, etc.), valves (e.g., polymericor carbon mechanical valves, tissue valves, valve designs includingpercutaneous, sewing cuff, and the like), embolic protection filters(including distal protection devices), vena cava filters, aneurysmexclusion devices, artificial hearts, cardiac jackets, and heart assistdevices (including left ventricle assist devices), implantabledefibrillators, electro-stimulation devices and leads (includingpacemakers, lead adapters and lead connectors), implanted medical devicepower supplies (e.g., batteries, etc.), peripheral cardiovasculardevices, atrial septal defect closures, left atrial appendage filters,valve annuloplasty devices (e.g., annuloplasty rings), mitral valverepair devices, vascular intervention devices, ventricular assist pumps,and vascular access devices (including parenteral feeding catheters,vascular access ports, central venous access catheters); surgicaldevices such as sutures of all types, staples, anastomosis devices(including anastomotic closures), suture anchors, hemostatic barriers,screws, plates, clips, vascular implants, tissue scaffolds,cerebro-spinal fluid shunts, shunts for hydrocephalus, drainage tubes,catheters including thoracic cavity suction drainage catheters, abscessdrainage catheters, biliary drainage products, and implantable pumps;orthopedic devices such as joint implants, acetabular cups, patellarbuttons, bone repair/augmentation devices, spinal devices (e.g.,vertebral disks and the like), bone pins, cartilage repair devices, andartificial tendons; dental devices such as dental implants and dentalfracture repair devices; drug delivery devices such as drug deliverypumps, implanted drug infusion tubes, drug infusion catheters, andintravitreal drug delivery devices; ophthalmic devices including orbitalimplants, glaucoma drain shunts and intraocular lenses; urologicaldevices such as penile devices (e.g., impotence implants), sphincter,urethral, prostate, and bladder devices (e.g., incontinence devices,benign prostate hyperplasia management devices, prostate cancerimplants, etc.), urinary catheters including indwelling (“Foley”) andnon-indwelling urinary catheters, and renal devices; syntheticprostheses such as breast prostheses and artificial organs (e.g.,pancreas, liver, lungs, heart, etc.); respiratory devices including lungcatheters; neurological devices such as neurostimulators, neurologicalcatheters, neurovascular balloon catheters, neuro-aneurysm treatmentcoils, and neuropatches; ear nose and throat devices such as nasalbuttons, nasal and airway splints, nasal tampons, ear wicks, eardrainage tubes, tympanostomy vent tubes, otological strips, laryngectomytubes, esophageal tubes, esophageal stents, laryngeal stents, salivarybypass tubes, and tracheostomy tubes; biosensor devices includingglucose sensors, cardiac sensors, intra-arterial blood gas sensors;oncological implants; and pain management implants.

Classes of non-implantable devices can include dialysis devices andassociated tubing, catheters, membranes, and grafts; autotransfusiondevices; vascular and surgical devices including atherectomy catheters,angiographic catheters, intraaortic balloon pumps, intracardiac suctiondevices, blood pumps, blood oxygenator devices (including tubing andmembranes), blood filters, blood temperature monitors, hemoperfusionunits, plasmapheresis units, transition sheaths, dialators, intrauterinepressure devices, clot extraction catheters, percutaneous transluminalangioplasty catheters, electrophysiology catheters, breathing circuitconnectors, stylets (vascular and non-vascular), coronary guide wires,peripheral guide wires; dialators (e.g., urinary, etc.); surgicalinstruments (e.g. scalpels and the like); endoscopic devices (such asendoscopic surgical tissue extractors, esophageal stethoscopes); andgeneral medical and medically related devices including blood storagebags, umbilical tape, membranes, gloves, surgical drapes, wounddressings, wound management devices, needles, percutaneous closuredevices, transducer protectors, pessary, uterine bleeding patches, PAPbrushes, clamps (including bulldog clamps), cannulae, cell culturedevices, materials for in vitro diagnostics, chromatographic supportmaterials, infection control devices, colostomy bag attachment devices,birth control devices; disposable temperature probes; and pledgets.

In some aspects, embodiments of the invention can include and beutilized in conjunction with ophthalmic devices. Suitable ophthalmicdevices in accordance with these aspects can provide bioactive agent toany desired area of the eye. In some aspects, the devices can beutilized to deliver bioactive agent to an anterior segment of the eye(in front of the lens), and/or a posterior segment of the eye (behindthe lens). Suitable ophthalmic devices can also be utilized to providebioactive agent to tissues in proximity to the eye, when desired.

In some aspects, embodiments of the invention can be utilized inconjunction with ophthalmic devices configured for placement at anexternal or internal site of the eye. Suitable external devices can beconfigured for topical administration of bioactive agent. Such externaldevices can reside on an external surface of the eye, such as the cornea(for example, contact lenses) or bulbar conjunctiva. In someembodiments, suitable external devices can reside in proximity to anexternal surface of the eye.

Devices configured for placement at an internal site of the eye canreside within any desired area of the eye. In some aspects, theophthalmic devices can be configured for placement at an intraocularsite, such as the vitreous. Illustrative intraocular devices include,but are not limited to, those described in U.S. Pat. Nos. 6,719,750 B2(“Devices for Intraocular Drug Delivery,” Varner et al.) and 5,466,233(“Tack for Intraocular Drug Delivery and Method for Inserting andRemoving Same,” Weiner et al.); U.S. Publication Nos. 2005/0019371 A1(“Controlled Release Bioactive Agent Delivery Device,” Anderson et al.),2004/0133155 A1 (“Devices for Intraocular Drug Delivery,” Varner etal.), 2005/0059956 A1 (“Devices for Intraocular Drug Delivery,” Varneret al.), and 2003/0014036 A1 (“Reservoir Device for Intraocular DrugDelivery,” Varner et al.); and U.S. application Ser. Nos. 11/204,195(filed Aug. 15, 2005, Anderson et al.), 11/204,271 (filed Aug. 15, 2005,Anderson et al.), 11/203,981 (filed Aug. 15, 2005, Anderson et al.),11/203,879 (filed Aug. 15, 2005, Anderson et al.), 11/203,931 (filedAug. 15, 2005, Anderson et al.); and related applications.

In some aspects, the ophthalmic devices can be configured for placementat a subretinal area within the eye. Illustrative ophthalmic devices forsubretinal application include, but are not limited to, those describedin U.S. Patent Publication No. 2005/0143363 (“Method for SubretinalAdministration of Therapeutics Including Steroids; Method for LocalizingPharmacodynamic Action at the Choroid and the Retina; and RelatedMethods for Treatment and/or Prevention of Retinal Diseases,” de Juan etal.); U.S. application Ser. No. 11/175,850 (“Methods and Devices for theTreatment of Ocular Conditions,” de Juan et al.); and relatedapplications.

Suitable ophthalmic devices can be configured for placement within anydesired tissues of the eye. For example, ophthalmic devices can beconfigured for placement at a subconjunctival area of the eye, such asdevices positioned extrasclerally but under the conjunctiva, such asglaucoma drainage devices and the like.

Hydrophobic Polymers

In an embodiment, the base layer can include a hydrophobic polymer. Onemethod of defining the hydrophobicity of a polymer is by the solubilityparameter (or Hildebrand parameter) of the polymer. The solubilityparameter describes the attractive strength between molecules of thematerial. The solubility parameter is represented by Equation 1:

δ=(ΔE ^(v) /V)^(1/2)  (Equation 1)

where

δ=solubility parameter ((cal/cm³)^(1/2))

δE^(v)=energy of vaporization (cal)

V=molar volume (cm³)

Solubility parameters cannot be calculated for polymers from heat ofvaporization data because of their nonvolatility. Accordingly,solubility parameters must be calculated indirectly. One method involvesidentifying solvents in which a polymer dissolves without a change inheat or volume and then defining the solubility parameter of the polymerto be the same as the solubility parameters of the identified solvents.A more complete discussion of solubility parameters and methods ofcalculating the same can be found in Brandup et al., Polymer Handbook,4th Ed., John Wiley & Sons, N.Y. (1999) beginning at VII p. 675.

As a general rule, the value of the solubility parameter δ is inverselyproportional to the degree of hydrophobicity of a polymer. Thus,polymers that are very hydrophobic may have a low solubility parametervalue. This general proposition is particularly applicable for polymershaving a glass transition temperature below physiological temperature.In an embodiment, hydrophobic polymers used with the invention have asolubility parameter less than about 11.0 (cal/cm³)^(1/2). In anembodiment, hydrophobic polymers used with the invention have asolubility parameter of less than about 10.0 (cal/cm³)^(1/2).

Degradable Polymers

In an embodiment, the base layer can include one or more degradablepolymers. The term “degradable” as used herein with reference topolymers, shall refer to those natural or synthetic polymers that breakdown under physiological conditions into constituent components over aperiod of time. By way of example, many degradable polymers includehydrolytically unstable linkages in the polymeric backbone. The cleavageof these unstable linkages leads to degradation of the polymer. Theterms “erodible”, “bioerodible”, “biodegradable” and “non-durable” shallbe used herein interchangeably with the term “degradable”. Degradablepolymers can include both natural or synthetic polymers. Examples ofdegradable polymers can include those with hydrolytically unstablelinkages in the polymeric backbone. Degradable polymers of the inventioncan include both those with bulk erosion characteristics and those withsurface erosion characteristics.

Synthetic degradable polymers can include: degradable polyesters (suchas poly(glycolic acid), poly(lactic acid), poly(lactic-co-glycolicacid), poly(dioxanone), polylactones (e.g., poly(caprolactone)),poly(3-hydroxybutyrate), poly(3-hydroxyvalerate), poly(valerolactone),poly(tartronic acid), poly(B-malonic acid), poly(propylene fumarate));degradable polyesteramides; degradable polyanhydrides (such aspoly(sebacic acid), poly(1,6-bis(carboxyphenoxy)hexane,poly(1,3-bis(carboxyphenoxy)propane); degradable polycarbonates (such astyrosine-based polycarbonates); degradable polyiminocarbonates;degradable polyarylates (such as tyrosine-based polyarylates);degradable polyorthoesters; degradable polyurethanes; degradablepolyphosphazenes; and degradable polyhydroxyalkanoates; and copolymersthereof.

Natural or naturally-based degradable polymers can includepolysaccharides and modified polysaccharides such as starch, cellulose,chitin, chitosan, and copolymers thereof.

Specific examples of degradable polymers include poly(ether ester)multiblock copolymers based on poly(ethylene glycol) (PEG) andpoly(butylene terephthalate) that can be described by the followinggeneral structure:

[—(OCH₂CH₂)_(n)—O—C(O)—C₆H₄—C(O)—]x[—O—(CH₂)₄—O—C(O)—C₆H₄—C(O)—]y,

where —C₆H₄— designates the divalent aromatic ring residue from eachesterified molecule of terephthalic acid, n represents the number ofethylene oxide units in each hydrophilic PEG block, x represents thenumber of hydrophilic blocks in the copolymer, and y represents thenumber of hydrophobic blocks in the copolymer. n can be selected suchthat the molecular weight of the PEG block is between about 300 andabout 4000. X and y can be selected so that the multiblock copolymercontains from about 55% up to about 80% PEG by weight. The blockcopolymer can be engineered to provide a wide array of physicalcharacteristics (e.g., hydrophilicity, adherence, strength,malleability, degradability, durability, flexibility) and active agentrelease characteristics (e.g., through controlled polymer degradationand swelling) by varying the values of n, x and y in the copolymerstructure.

Degradable polyesteramides can include those formed from the monomersOH-x-OH, z, and COOH-y-COOH, wherein x is alkyl, y is alkyl, and z isleucine or phenylalanine.

Degradable polymeric materials can also be selected from: (a)non-peptide polyamino polymers; (b) polyiminocarbonates; (c) aminoacid-derived polycarbonates and polyarylates; and (d) poly(alkyleneoxide) polymers.

In an embodiment, the degradable polymeric material is composed of anon-peptide polyamino acid polymer. Exemplary non-peptide polyamino acidpolymers are described, for example, in U.S. Pat. No. 4,638,045(“Non-Peptide Polyamino Acid Bioerodible Polymers,” Jan. 20, 1987).Generally speaking, these polymeric materials are derived from monomers,including two or three amino acid units having one of the following twostructures illustrated below:

wherein the monomer units are joined via hydrolytically labile bonds atnot less than one of the side groups R₁, R₂, and R₃, and where R₁, R₂,R₃ are the side chains of naturally occurring amino acids; Z is anydesirable amine protecting group or hydrogen; and Y is any desirablecarboxyl protecting group or hydroxyl. Each monomer unit comprisesnaturally occurring amino acids that are then polymerized as monomerunits via linkages other than by the amide or “peptide” bond. Themonomer units can be composed of two or three amino acids united througha peptide bond and thus comprise dipeptides or tripeptides. Regardlessof the precise composition of the monomer unit, all are polymerized byhydrolytically labile bonds via their respective side chains rather thanvia the amino and carboxyl groups forming the amide bond typical ofpolypeptide chains. Such polymer compositions are nontoxic, aredegradable, and can provide zero-order release kinetics for the deliveryof active agents in a variety of therapeutic applications. According tothese aspects, the amino acids are selected from naturally occurringL-alpha amino acids, including alanine, valine, leucine, isoleucine,proline, serine, threonine, aspartic acid, glutamic acid, asparagine,glutamine, lysine, hydroxylysine, arginine, hydroxyproline, methionine,cysteine, cystine, phenylalanine, tyrosine, tryptophan, histidine,citrulline, ornithine, lanthionine, hypoglycin A, β-alanine, γ-aminobutyric acid, α aminoadipic acid, canavanine, venkolic acid,thiolhistidine, ergothionine, dihydroxyphenylalanine, and other aminoacids well recognized and characterized in protein chemistry.

Degradable polymers of the invention can also include polymerizedpolysaccharides such as those described in U.S. Publ. Pat. ApplicationNo. 2005/0255142, entitled “COATINGS FOR MEDICAL ARTICLES INCLUDINGNATURAL BIODEGRADABLE POLYSACCHARIDES”, U.S. Publ. Pat. Application No.2007/0065481, entitled “COATINGS INCLUDING NATURAL BIODEGRADABLEPOLYSACCHARIDES AND USES THEREOF”, and in U.S. Application No.60/782,957, entitled “HYDROPHOBIC DERIVATIVES OF NATURAL BIODEGRADABLEPOLYSACCHARIDES”, all of which are herein incorporated by reference.

Degradable polymers of the invention can also include dextran basedpolymers such as those described in U.S. Pat. No. 6,303,148, entitled“PROCESS FOR THE PREPARATION OF A CONTROLLED RELEASE SYSTEM”. Exemplarydextran based degradable polymers including those available commerciallyunder the trade name OCTODEX.

Degradable polymers of the invention can further includecollagen/hyaluronic acid polymers.

Degradable polymers of the invention can include multi-block copolymers,comprising at least two hydrolysable segments derived from pre-polymersA and B, which segments are linked by a multi-functional chain-extenderand are chosen from the pre-polymers A and B, and triblock copolymersABA and BAB, wherein the multi-block copolymer is amorphous and has oneor more glass transition temperatures (Tg) of at most 37° C. (Tg) atphysiological (body) conditions. The pre-polymers A and B can be ahydrolysable polyester, polyetherester, polycarbonate,polyestercarbonate, polyanhydride or copolymers thereof, derived fromcyclic monomers such as lactide (L,D or L/D), glycolide, ε-caprolactone,δ-valerolactone, trimethylene carbonate, tetramethylene carbonate,1,5-dioxepane-2-one, 1,4-dioxane-2-one (para-dioxanone) or cyclicanhydrides (oxepane-2,7-dione). The composition of the pre-polymers canbe chosen in such a way that the maximum glass transition temperature ofthe resulting copolymer is below 37° C. at body conditions. To fulfillthe requirement of a Tg below 37° C., some of the above-mentionedmonomers or combinations of monomers can be more preferred than others.This may by itself lower the Tg, or the pre-polymer is initiated with apolyethylene glycol with sufficient molecular weight to lower the glasstransition temperature of the copolymer. The degradable multi-blockcopolymers can include hydrolysable sequences being amorphous and thesegments can be linked by a multifunctional chain-extender, the segmentshaving different physical and degradation characteristics. For example,a multi-block co-polyester consisting of a glycolide-ε-caprolactonesegment and a lactide-glycolide segment can be composed of two differentpolyester pre-polymers. By controlling the segment monomer composition,segment ratio and length, a variety of polymers with properties that caneasily be tuned can be obtained.

Non-Degradable Polymers

Embodiments of the invention can include one or more non-degradable(durable) polymers in the base layer. In an embodiment, thenon-degradable polymer includes a plurality of polymers, including afirst polymer and a second polymer. When the coating solution containsonly one polymer, it can be either a first or second polymer asdescribed herein. As used herein, term “(meth)acrylate” when used indescribing polymers shall mean the form including the methyl group(methacrylate) or the form without the methyl group (acrylate).

First polymers of the invention can include a polymer selected from thegroup consisting of poly(alkyl(meth)acrylates) andpoly(aromatic(meth)acrylates), where “(meth)” will be understood bythose skilled in the art to include such molecules in either the acrylicand/or methacrylic form (corresponding to the acrylates and/ormethacrylates, respectively). An exemplary first polymer is poly(n-butylmethacrylate) (pBMA). Such polymers are available commercially, e.g.,from Aldrich, with molecular weights ranging from about 200,000 Daltonsto about 320,000 Daltons, and with varying inherent viscosity,solubility, and form (e.g., as crystals or powder). In some embodiments,poly(n-butyl methacrylate) (pBMA) is used with a molecular weight ofabout 200,000 Daltons to about 300,000 Daltons.

Examples of suitable first polymers also include polymers selected fromthe group consisting of poly(aryl(meth)acrylates),poly(aralkyl(meth)acrylates), and poly(aryloxyalkyl(meth)acrylates).Such terms are used to describe polymeric structures wherein at leastone carbon chain and at least one aromatic ring are combined withacrylic groups, typically esters, to provide a composition. Inparticular, exemplary polymeric structures include those with arylgroups having from 6 to 16 carbon atoms and with weight averagemolecular weights from about 50 to about 900 kilodaltons. Suitablepoly(aralkyl(meth)acrylates), poly(arylalky(meth)acrylates) orpoly(aryloxyalkyl(meth)acrylates) can be made from aromatic estersderived from alcohols also containing aromatic moieties. Examples ofpoly(aryl(meth)acrylates) include poly(9-anthracenyl methacrylate),poly(chlorophenylacrylate), poly(methacryloxy-2-hydroxybenzophenone),poly(methacryloxybenzotriazole), poly(naphthylacrylate) and-methacrylate), poly(4-nitrophenyl acrylate), poly(pentachloro(bromo,fluoro)acrylate) and -methacrylate), and poly(phenyl acrylate) and-methacrylate). Examples of poly(aralkyl(meth)acrylates) includepoly(benzyl acrylate) and -methacrylate), poly(2-phenethyl acrylate) and-methacrylate, and poly(1-pyrenylmethyl methacrylate). Examples ofpoly(aryloxyalkyl(meth)acrylates) include poly(phenoxyethyl acrylate)and -methacrylate), and poly(polyethylene glycol phenyl ether acrylates)and -methacrylates with varying polyethylene glycol molecular weights.

Examples of suitable second polymers are available commercially andinclude poly(ethylene-co-vinyl acetate) (pEVA) having vinyl acetateconcentrations of between about 10% and about 50% (12%, 14%, 18%, 25%,33% versions are commercially available), in the form of beads, pellets,granules, etc. pEVA co-polymers with lower percent vinyl acetate becomeincreasingly insoluble in typical solvents, whereas those with higherpercent vinyl acetate become decreasingly durable.

An exemplary polymer mixture includes mixtures of pBMA and pEVA. Thismixture of polymers can be used with absolute polymer concentrations(i.e., the total combined concentrations of both polymers in the coatingmaterial), of between about 0.25 wt. % and about 99 wt. %. This mixturecan also be used with individual polymer concentrations in the coatingsolution of between about 0.05 wt. % and about 99 wt. %. In oneembodiment the polymer mixture includes pBMA with a molecular weight offrom 100 kilodaltons to 900 kilodaltons and a pEVA copolymer with avinyl acetate content of from 24 to 36 weight percent. In an embodimentthe polymer mixture includes pBMA with a molecular weight of from 200kilodaltons to 300 kilodaltons and a pEVA copolymer with a vinyl acetatecontent of from 24 to 36 weight percent. The concentration of the activeagent or agents dissolved or suspended in the coating mixture can rangefrom 0.01 to 99 percent, by weight, based on the weight of the finalcoating material.

Second polymers can also comprise one or more polymers selected from thegroup consisting of (i) poly(alkylene-co-alkyl(meth)acrylates, (ii)ethylene copolymers with other alkylenes, (iii) polybutenes, (iv)diolefin derived non-aromatic polymers and copolymers, (v) aromaticgroup-containing copolymers, and (vi) epichlorohydrin-containingpolymers.

Poly(alkylene-co-alkyl(meth)acrylates) include those copolymers in whichthe alkyl groups are either linear or branched, and substituted orunsubstituted with non-interfering groups or atoms. Such alkyl groupscan comprise from 1 to 8 carbon atoms, inclusive. Such alkyl groups cancomprise from 1 to 4 carbon atoms, inclusive. In an embodiment, thealkyl group is methyl. In some embodiments, copolymers that include suchalkyl groups can comprise from about 15% to about 80% (wt) of alkylacrylate. When the alkyl group is methyl, the polymer contains fromabout 20% to about 40% methyl acrylate in some embodiments, and fromabout 25% to about 30% methyl acrylate in a particular embodiment. Whenthe alkyl group is ethyl, the polymer contains from about 15% to about40% ethyl acrylate in an embodiment, and when the alkyl group is butyl,the polymer contains from about 20% to about 40% butyl acrylate in anembodiment.

Alternatively, second polymers can comprise ethylene copolymers withother alkylenes, which in turn, can include straight and branchedalkylenes, as well as substituted or unsubstituted alkylenes. Examplesinclude copolymers prepared from alkylenes that comprise from 3 to 8branched or linear carbon atoms, inclusive. In an embodiment, copolymersprepared from alkylene groups that comprise from 3 to 4 branched orlinear carbon atoms, inclusive. In a particular embodiment, copolymersprepared from alkylene groups containing 3 carbon atoms (e.g., propene).By way of example, the other alkylene is a straight chain alkylene(e.g., 1-alkylene). Exemplary copolymers of this type can comprise fromabout 20% to about 90% (based on moles) of ethylene. In an embodiment,copolymers of this type comprise from about 35% to about 80% (mole) ofethylene. Such copolymers will have a molecular weight of between about30 kilodaltons to about 500 kilodaltons. Exemplary copolymers areselected from the group consisting of poly(ethylene-co-propylene),poly(ethylene-co-1-butene), polyethylene-co-1-butene-co-1-hexene) and/orpoly(ethylene-co-1-octene).

“Polybutenes” include polymers derived by homopolymerizing or randomlyinterpolymerizing isobutylene, 1-butene and/or 2-butene. The polybutenecan be a homopolymer of any of the isomers or it can be a copolymer or aterpolymer of any of the monomers in any ratio. In an embodiment, thepolybutene contains at least about 90% (wt) of isobutylene or 1-butene.In a particular embodiment, the polybutene contains at least about 90%(wt) of isobutylene. The polybutene may contain non-interfering amountsof other ingredients or additives, for instance it can contain up to1000 ppm of an antioxidant (e.g., 2,6-di-tert-butyl-methylphenol). Byway of example, the polybutene can have a molecular weight between about150 kilodaltons and about 1,000 kilodaltons. In an embodiment, thepolybutene can have between about 200 kilodaltons and about 600kilodaltons. In a particular embodiment, the polybutene can have betweenabout 350 kilodaltons and about 500 kilodaltons. Polybutenes having amolecular weight greater than about 600 kilodaltons, including greaterthan 1,000 kilodaltons are available but are expected to be moredifficult to work with.

Additional alternative second polymers include diolefin-derived,non-aromatic polymers and copolymers, including those in which thediolefin monomer used to prepare the polymer or copolymer is selectedfrom butadiene (CH₂═CH—CH═CH₂) and/or isoprene (CH₂═CH—C(CH₃)═CH₂). Inan embodiment, the polymer is a homopolymer derived from diolefinmonomers or is a copolymer of diolefin monomer with non-aromaticmono-olefin monomer, and optionally, the homopolymer or copolymer can bepartially hydrogenated. Such polymers can be selected from the groupconsisting of polybutadienes prepared by the polymerization of cis-,trans- and/or 1,2-monomer units, or from a mixture of all threemonomers, and polyisoprenes prepared by the polymerization of cis-1,4-and/or trans-1,4-monomer units. Alternatively, the polymer is acopolymer, including graft copolymers, and random copolymers based on anon-aromatic mono-olefin monomer such as acrylonitrile, and analkyl(meth)acrylate and/or isobutylene. In an embodiment, when themono-olefin monomer is acrylonitrile, the interpolymerized acrylonitrileis present at up to about 50% by weight; and when the mono-olefinmonomer is isobutylene, the diolefin is isoprene (e.g., to form what iscommercially known as a “butyl rubber”). Exemplary polymers andcopolymers have a molecular weight between about 150 kilodaltons andabout 1,000 kilodaltons. In an embodiment, polymers and copolymers havea molecular weight between about 200 kilodaltons and about 600kilodaltons.

Additional alternative second polymers include aromatic group-containingcopolymers, including random copolymers, block copolymers and graftcopolymers. In an embodiment, the aromatic group is incorporated intothe copolymer via the polymerization of styrene. In a particularembodiment, the random copolymer is a copolymer derived fromcopolymerization of styrene monomer and one or more monomers selectedfrom butadiene, isoprene, acrylonitrile, a C₁-C₄ alkyl(meth)acrylate(e.g., methyl methacrylate) and/or butene. Useful block copolymersinclude copolymer containing (a) blocks of polystyrene, (b) blocks of anpolyolefin selected from polybutadiene, polyisoprene and/or polybutene(e.g., isobutylene), and (c) optionally a third monomer (e.g., ethylene)copolymerized in the polyolefin block. The aromatic group-containingcopolymers contain about 10% to about 50% (wt.) of polymerized aromaticmonomer and the molecular weight of the copolymer is from about 300kilodaltons to about 500 kilodaltons. In an embodiment, the molecularweight of the copolymer is from about 100 kilodaltons to about 300kilodaltons.

Additional alternative second polymers include epichlorohydrinhomopolymers and poly(epichlorohydrin-co-alkylene oxide) copolymers. Inan embodiment, in the case of the copolymer, the copolymerized alkyleneoxide is ethylene oxide. By way of example, epichlorohydrin content ofthe epichlorohydrin-containing polymer is from about 30% to 100% (wt).In an embodiment, epichlorohydrin content is from about 50% to 100%(wt). In an embodiment, the epichlorohydrin-containing polymers have amolecular weight from about 100 kilodaltons to about 300 kilodaltons.

Non-degradable polymers can also include those described in U.S. Pat.App. No. 2007/0026037, entitled “DEVICES, ARTICLES, COATINGS, ANDMETHODS FOR CONTROLLED ACTIVE AGENT RELEASE OR HEMOCOMPATIBILITY”, thecontents of which is herein incorporated by reference. As a specificexample, non-degradable polymers can include random copolymers of butylmethacrylate-co-acrylamido-methyl-propane sulfonate (BMA-AMPS). In someembodiments, the random copolymer can include AMPS in an amount equal toabout 0.5 mol. % to about 40 mol.

The present invention may be better understood with reference to thefollowing examples. These examples are intended to be representative ofspecific embodiments of the invention, and are not intended as limitingthe scope of the invention.

EXAMPLES Example 1 Parylene Coat Over Non-Degradable Hydrophobic Matrix

Poly-n-butylmethacrylate (PBMA) and polyethylene-co-vinyl acetate (PEVA)were combined in a solvent of chloroform to form a non-degradablepolymer solution having 10 mg/ml PBMA and 10 mg/ml PEVA (total solidsconcentration of 20 mg/ml).

IgG rabbit anti-goat antibodies were obtained from Sigma-Aldrich, St.Louis, Mo. The IgG rabbit anti-goat antibodies were combined withnon-specific IgG rabbit antibodies at a ration of 10:1 non-specific tospecific in PBS (phosphate buffered saline) to form an IgG solution.

MP-35N alloy coils (N=7) were simultaneously coated with both thenon-degradable polymer solution and the IgG solution. The non-degradablepolymer solution was applied onto the exterior surface of a firstultrasonic nozzle (60 KHz ultrasonic nozzle from Sono-Tek, Milton, N.Y.,operating at about 0.5 to 1.5 watts) at a rate of 0.025 mL/minute.Simultaneously, the IgG solution was applied onto the exterior surfaceof a second ultrasonic nozzle (60 KHz ultrasonic nozzle from Sono-Tek,Milton, N.Y., operating at about 0.5 to 1.5 watts) at a rate of 0.025mL/minute. Both ultrasonic spray nozzles were directed at the coils.Coils were then passed back and forth under the spray nozzles androtated a plurality of times. This treatment resulted in a coatinghaving approximately 50 wt. % IgG, 25 wt. % PBMA, and 25 wt. % PEVA. Thetotal protein loading (specific and non-specific IgG) was calculated tobe about 656 μg on average. The total active protein loading wascalculated to be about 66 μg on average. After coating, the coils weredried in a vacuum chamber at ambient temperature for 24 hours.

Next, a layer of parylene C was vapor deposited onto two sets of coils.Specifically, for a first set (N=2) 0.5 grams of parylene C dimer(Specialty Coating Systems, Indianapolis, Ind.) was loaded into a vapordeposition system PDS-2010 LABCOTER® (Specialty Coating Systems,Indianapolis, Ind.). A coating cycle was then initiated and a layer ofparylene approximately 0.1 to 0.3 microns thick was deposited onto thefirst set of coils under vacuum. For a second set (N=2), 1.0 gram ofparylene C dimer was loaded into the vapor deposition system. A coatingcycle was then initiated and a layer of parylene approximately 0.4 to0.6 microns thick was deposited onto the second set of coils undervacuum. For a control set (N=3), no parylene was deposited.

The elution rate of the IgG antibodies from the three sets of coils wasthen evaluated. Coils were placed in microcentrifuge tubes in 500 μL ofa solution of 1×PBS. At predetermined intervals for 63 days, 200 μL ofthe eluent solution was removed, divided into two 100 μL aliquots, andplaced into two 96 well plates. The remaining 300 μL was removed fromthe microcentrifuge tube, and 0.5 mL of fresh eluent solution (1×PBS)was added to the microcentrifuge tube having the coil. The eluentsamples were also analyzed for total IgG release (specific andnon-specific) using the Bradford method assay (dye obtained from SigmaChemical Co., St. Louis, Mo.). The results are shown in Table 1 belowand in FIG. 6.

TABLE 1 Cumulative IgG Release (% of Total IgG) Days Control 0.5 gparylene 1.0 g parylene 0 0.00% 0.00% 0.00% 0.29 16.95% 2.81% 0.63% 3.725.44% 18.54% 11.63% 4.78 26.92% 21.38% 14.59% 5.78 27.90% 23.11% 16.54%

This example shows that parylene can be used as a top layer and can bemade porous enough to allow for the elution of a macromolecule such as apeptide or a protein. This example further shows that the amount ofparylene deposited can affect the elution rate of the resulting coating.

Example 2 Effects of Vacuum Drying on Elution Rate

Poly-n-butylmethacrylate (PBMA) and polyethylene-co-vinyl acetate (PEVA)were combined in a solvent of chloroform to form a non-degradablepolymer solution having 12.5 mg/ml PBMA and 12.5 mg/ml PEVA (totalsolids concentration of 25 mg/ml).

IgG rabbit anti-goat antibodies were obtained from Sigma-Aldrich, St.Louis, Mo. The IgG rabbit anti-goat antibodies were combined withnon-specific IgG rabbit antibodies at a ration of 10:1 non-specific tospecific in PBS (phosphate buffered saline) to form an IgG solution witha concentration of 20 mg/ml of IgG.

MP-35N alloy coils (N=4) were segregated into two experimental groups(Group 1 (N=2) and Group 2 (N=4)). The non-degradable polymer solutionand the IgG solution were simultaneously deposited onto the coils.Specifically, the non-degradable polymer solution was applied onto theexterior surface of a first ultrasonic nozzle (60 KHz ultrasonic nozzlefrom Sono-Tek, Milton, N.Y., operating at about 0.5 to 1.5 watts) at arate of 0.04 mL/minute. Simultaneously, the IgG solution was appliedonto the exterior surface of a second ultrasonic nozzle (60 KHzultrasonic nozzle from Sono-Tek, Milton, N.Y., operating at about 0.5 to1.5 watts) at a rate of 0.02 mL/minute. Both ultrasonic spray nozzleswere directed at the coils. The coils were passed back and forth underthe spray nozzles and rotated a plurality of times. This treatmentresulted in a coating having approximately 40 wt. % IgG, 30 wt. % PBMA,and 30 wt. % PEVA. The total protein loading (specific and non-specificIgG) was calculated to be about 710 μg on average for the coils of Group1 and about 685 μg on average for the coils of Group 2.

After coating with the non-degradable polymer solution and the IgGsolution, the coils of Group 1 were dried in a vacuum chamber at ambienttemperature for about 12-16 hours. However, the coils of Group 2 werenot dried in a vacuum chamber. Rather, the coils of Group 2 were driedfor the same length of time under ambient temperature and pressureconditions.

Next, a layer of parylene C was vapor deposited onto the coils of Group1 and Group 2. Specifically, 2.0 grams of parylene C dimer (SpecialtyCoating Systems, Indianapolis, Ind.) was loaded into a vapor depositionsystem PDS-2010 LABCOTER® (Specialty Coating Systems, Indianapolis,Ind.). A coating cycle was then initiated and a layer of paryleneapproximately 0.8 to 1.2 microns thick was deposited onto the coils ofboth experimental groups. Specifically, about 59.5 μg of parylene wasdeposited onto the coils of Group 1 and about 57 μg of parylene wasdeposited onto the coils of Group 2.

The elution rate of the IgG antibodies from the coils of Group 1 andGroup 2 was then evaluated as described above in Example 1. The resultsare shown below in Table 2 and in FIG. 7.

TABLE 2 Cumulative IgG Release (% of Total IgG) Days Vacuum DriedNot-Vacuum Dried 0 0.00% 0.00% 1 0.76% 0.79% 4 2.37% 3.00% 7 5.09% 6.27%22 11.78% 13.77% 28 12.72% 16.14%

This example shows that treatment of a material before a parylene layeris applied can affect the resulting elution rate of an active agent.Specifically, this example shows that exposing an underlying material toconditions, such as vacuum conditions, that promote vaporization ofcertain components before a parylene layer is applied can slow down theelution rate of an active agent from the resulting coating.

It should be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to a composition containing “a compound” includes a mixture oftwo or more compounds. It should also be noted that the term “or” isgenerally employed in its sense including “and/or” unless the contentclearly dictates otherwise.

It should also be noted that, as used in this specification and theappended claims, the phrase “configured” describes a system, apparatus,or other structure that is constructed or configured to perform aparticular task or adopt a particular configuration to. The phrase“configured” can be used interchangeably with other similar phrases suchas arranged and configured, constructed and arranged, constructed,manufactured and arranged, and the like.

All publications and patent applications in this specification areindicative of the level of ordinary skill in the art to which thisinvention pertains. All publications and patent applications are hereinincorporated by reference to the same extent as if each individualpublication or patent application was specifically and individuallyindicated by reference.

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A method of applying an elution control coating to a substratecomprising: depositing a coating solution onto the substrate to form abase layer, the coating solution comprising an active agent, a polymer,and a solvent; selecting a desired concentration of the solvent based ona desired elution rate; removing solvent from the base layer to reach adesired concentration of the solvent; and depositing a layer of paryleneon the base layer.
 2. The method of claim 1, wherein depositing acoating solution onto the substrate to form a base layer comprisesspraying a coating solution onto the substrate.
 3. The method of claim1, the active agent comprising a macromolecule.
 4. The method of claim1, the active agent selected from the group consisting of peptides andproteins.
 5. The method of claim 1, the active agent selected from thegroup consisting of antibodies and antibody derivatives.
 6. The methodof claim 1, the solvent comprising a non-polar solvent.
 7. The method ofclaim 1, the solvent comprising a polar solvent.
 8. The method of claim1, wherein depositing a coating solution onto a substrate to form a baselayer comprises simultaneously spraying a first coating solution ontothe substrate from a first spray head and spraying a second coatingsolution onto the substrate from a second spray head.
 9. The method ofclaim 8, the first coating solution comprising the active agent and thesecond coating solution comprising the polymer.
 10. The method of claim1, the polymer comprising a degradable polymer and a non-degradablepolymer, the first coating solution comprising the degradable polymerand the active agent and the second coating solution comprisingnon-degradable polymer.
 11. The method of claim 1, wherein removingsolvent from the base layer comprises inserting the base layer and thesubstrate into a vacuum chamber.
 12. The method of claim 1, whereinremoving solvent from the base layer comprises inserting the base layerand the substrate into a vacuum chamber for a period of time greaterthan about 30 minutes.
 13. A method of depositing a multi-layer elutioncontrol coating onto a substrate comprising: depositing a coatingsolution onto the substrate to form a base layer, the coating solutioncomprising an active agent, a polymer, and a solvent; storing thesubstrate and base layer under vacuum for a period of time greater thanabout 30 minutes to form a degassed base layer; and depositing a layerof parylene on the degassed base layer.
 14. A medical device comprising:a substrate; a base layer disposed on the substrate, the base layercomprising a polymeric matrix and an active agent, the active agentdispersed within the polymeric matrix, the active agent selected fromthe group consisting of peptides, proteins, antibodies, and antibodyderivatives; and a porous layer disposed directly on the base layer, theporous layer comprising parylene.
 15. The medical device of claim 14,the base layer comprising a degradable polymer and a non-degradablepolymer, the degradable polymer and the non-degradable polymer formingan interpenetrating network, the active agent dispersed within thedegradable polymer.
 16. The medical device of claim 14, the polymericmatrix comprising a hydrophobic polymer.
 17. The medical device of claim14, the polymeric matrix comprising poly-n-butylmethacrylate andpolyethylene-co-vinyl acetate.
 18. The medical device of claim 14, thebase layer having a thickness of between about 0.5 microns and about 100microns.
 19. The medical device of claim 14, the top layer comprisingpoly(2-chloro-paraxylylene).
 20. The medical device of claim 14configured to elute about 0.1 μg/day to about 3.0 μg/day of the peptidefor a period of time of at least about 30 days.